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Details for Patent: 5,783,701

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Details for Patent: 5,783,701

Title: Sulfonamide inhibitors of aspartyl protease
Abstract:The present invention relates to a novel class of sulfonamides which are aspartyl protease inhibitors. In one embodiment, this invention relates to a novel class of HIV aspartyl protease inhibitors characterized by specific structural and physicochemical features. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting HIV-1 and HIV-2 protease activity and consequently, may be advantageously used as anti-viral agents against the HIV-1 and HIV-2 viruses. This invention also relates to methods for inhibiting the activity of HIV aspartyl protease using the compounds of this invention and methods for screening compounds for anti-HIV activity.
Inventor(s): Tung; Roger D. (Arlington, MA), Murcko; Mark A. (Holliston, MA), Bhisetti; Govinda Rao (Lexington, MA)
Assignee: Vertex Pharmaceuticals, Incorporated (Cambridge, MA)
Filing Date:Feb 23, 1995
Application Number:08/393,460
Claims:1. A compound of formula I: ##STR654## wherein: A is selected from the group consisting of H; Ht; --R.sup.1 --Ht; --R.sup.1 --C.sub.1 -C.sub.6 alkyl, which is optionally substituted with one to two groups independently selected from the group consisting of hydroxy, C.sub.1 -C.sub.4 alkoxy, Ht, --O--Ht, --NR.sup.2 --CO--N(R.sup.2)(R.sup.2) and --CO--N(R.sup.2)(R.sup.2); and --R.sup.1 --C.sub.2 -C.sub.6 alkenyl, which is optionally substituted with one to two groups independently selected from the group consisting of hydroxy, C.sub.1 -C.sub.4 alkoxy, Ht, --O--Ht, --NR.sup.2 --CO--N(R.sup.2)(R.sup.2) and --CO--N(R.sup.2)(R.sup.2);

each R.sup.1 is independently selected from the group consisting of --C(O)--, S(O).sub.2 --, --C(O)--C(O)--, --O--C(O)--, --O--S(O).sub.2, --NR.sup.2 --S(O).sub.2 --, --NR.sup.2 --C(O)-- and --NR.sup.2 --C(O)--C(O)--;

each Ht is independently selected from the group consisting of C.sub.3 -C.sub.7 cycloalkyl; C.sub.5 -C.sub.7 cycloalkenyl; C.sub.6 -C.sub.10 aryl; and 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from N and O, with the proviso that said heterocycle may not be a pyridyl group and wherein said heterocycle is optionally benzofused; and wherein any member of said Ht is optionally substituted with one to two substituents independently selected from the group consisting of oxo, --OR.sup.2, --R.sup.2, --N(R.sup.2)(R.sup.2), --R.sup.2 --OH, --CN, --CO.sub.2 R.sup.2, --C(O)--N(R.sup.2)(R.sup.2), --S(O).sub.2 --N(R.sup.2)(R.sup.2), --N(R.sup.2)--C(O)--R.sub.2, --C(O)--R.sup.2, --S(O).sub.n --R.sup.2, --OCF.sub.3, --S(O).sub.n --R.sup.7, methylenedioxy, --N(R.sup.2)--S(O).sub.2 (R.sup.2), halo, --CF.sub.3, --NO.sub.2, R.sup.7 and --O--R.sup.7 ;

each R.sup.2 is independently selected from the group consisting of H and C.sub.1 -C.sub.3 alkyl optionally substituted with R.sup.7 ;

B, when present, is --N(R.sup.2)--C(R.sup.3)(R.sup.3)--C(O)--;

x is 0 or 1;

each R.sup.3 is independently selected from the group consisting of H, Ht, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.6 cycloalkyl and C.sub.5 -C.sub.6 cycloalkenyl, wherein any member of said R.sup.3, except H, is optionally substituted with one to two substituents independently selected from the group consisting of --OR.sup.2, --C(O)--NH--R.sup.2, --S(O).sub.n --N(R.sup.2)(R.sup.2), Het, --CN, --SR.sup.2, --CO.sub.2 R.sup.2, and NR.sup.2 --C(O)--R.sup.2 ;

each n is independently 1 or 2;

D and D' are independently selected from the group consisting of R.sup.7 ; C.sub.1 -C.sub.4 alkyl substituted with C.sub.3 -C.sub.6 cycloalkyl, --O--R.sup.7 or R.sup.7, and optionally substituted with one additional substituent selected from C.sub.3 -C.sub.6 cycloalkyl, --O--R.sup.7, R.sup.7, OR.sup.2 or --R.sup.3 ; C.sub.2 -C.sub.4 alkenyl substituted with C.sub.3 -C.sub.6 cycloalkyl, --O--R.sup.7 or R.sup.7, and optionally substituted with one additional substituent selected from C.sub.3 -C.sub.6 cycloalkyl, --O--R.sup.7, R.sup.7, OR.sup.2 or --R.sup.3 ; C.sub.3 -C.sub.6 cycloalkyl, which is optionally substituted with or fused with R.sup.7 ; and C.sub.5 -C.sub.6 cycloalkenyl, which is optionally substituted with or fused with R.sup.7 ;

each R.sup.7 is independently selected from the group consisting of phenyl and 3-6 membered carbocyclic ring, wherein said carbocyclic ring may be saturated or unsaturated and wherein R.sup.7 is optionally substituted with one to two groups independently selected from the group consisting of oxo, --OR.sup.2, --R.sup.2, --N(R.sup.2)(R.sup.2), --N(R.sup.2)--C(O)--R.sup.2, --R.sup.2 --OH, --CN, --CO.sub.2 R.sup.2, --C(O)--N(R.sup.2)(R.sup.2), halo and --CF.sub.3 ;

E is a 5-membered heterocyclic ring containing one S and optionally containing N as an additional heteroatom, wherein said heterocyclic ring is optionally substituted with one to two groups independently selected from the group consisting of --CH.sub.3, R.sup.4 and Ht; and

each R.sup.4 is independently selected from the group consisting of --OR.sup.2, --C(O)--NHR.sup.2, --S(O).sub.2 --NHR.sup.2, halo, --NR.sup.2 --C(O)--R.sup.2 and --CN.

2. The compound according to claim 1, wherein said compound has the structure of formula XXII: ##STR655## wherein A, D' and E are defined as in claim 1.

3. The compound according to claim 1, wherein said compound has the structure of formula XXIII: ##STR656## wherein x, Ht, R.sup.3, D' and E are defined as in claim 1.

4. The compound according to claim 1, wherein:

A is selected from the group consisting of H; --R.sup.1 --Ht; --R.sup.1 --C.sub.1 -C.sub.6 alkyl, which is optionally substituted with one to two groups independently selected from the group consisting of hydroxy, C.sub.1 -C.sub.4 alkoxy, Ht and --O--Ht; and --R.sup.1 --C.sub.2 -C.sub.6 alkenyl, which is optionally substituted with one to two groups independently selected from the group consisting of hydroxy, C.sub.1 -C.sub.4 alkoxy, Ht and --O--Ht;

each R.sup.1 is independently selected from the group consisting of --C(O)--, --S(O).sub.2 --, --C(O)--C(O)--, --O--CO--, --O--S(O).sub.2 -- and --NR.sup.2 --S(O).sub.2 --;

each Ht is independently selected from the group consisting of C.sub.3 -C.sub.7 cycloalkyl; C.sub.5 -C.sub.7 cycloalkenyl; C.sub.6 -C.sub.10 aryl; and 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from N and O, with the proviso that said heterocycle may not be a pyridyl group and wherein said heterocycle is optionally benzofused; and wherein any member of said Ht is optionally substituted with one to two substituents independently selected from the group consisting of oxo, --OR.sup.2, --R.sup.2, --N(R.sup.2).sub.2, --R.sup.2 --OH, --CN, --CO.sub.2 R.sup.2, --C(O)--N(R.sup.2).sub.2 and --S(O).sub.2 --N(R.sup.2).sub.2 ;

B, when presents is --NH--CH(R.sup.3)--C(O)--;

x is 0 or 1;

each R.sup.3 is independently selected from the group consisting of Ht, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.6 cycloalkyl and C.sub.5 -C.sub.6 cycloalkenyl, wherein any member of said R.sup.3 is optionally substituted with one to two substituents independently selected from the group consisting of --OR.sup.2, --C(O)--NH--R.sup.2, --S(O).sub.n --N(R.sup.2).sub.2, Ht and --CN;

n is 1 or 2; and

D and D' are independently selected from the group consisting of R.sup.7 ; C.sub.1 -C.sub.4 alkyl substituted with C.sub.3 -C.sub.6 cycloalkyl, --O--R.sup.7 or R.sup.7 ; C.sub.2 -C.sub.4 alkenyl substituted with C.sub.3 -C.sub.6 cycloalkyl, --O--R.sup.7 or R.sup.7, and optionally substituted with one additional substituent selected from C.sub.3 -C.sub.6 cycloalkyl, --O--R.sup.7, R.sup.7, OR.sup.2 or --R.sup.3 ; C.sub.3 -C.sub.6 cycloalkyl, which is optionally substituted with or fused with R.sup.7 ; and C.sub.5 -C.sub.6 cycloalkenyl, which is optionally substituted with or fused with R.sup.7 ; with the proviso that when D is attached to N, D may not be methyl or C.sub.2 alkenyl.

5. The compound according to claim 2 or 3, wherein:

A is R.sup.1 --Ht; and

D' is selected from the group consisting of C.sub.1 -C.sub.3 alkyl and C.sub.3 alkenyl, wherein said alkyl or alkenyl is substituted with one to two groups independently selected from the group consisting of C.sub.3 -C.sub.6 cycloalkyl, --O--R.sup.7 and R.sup.7, and optionally substituted with one additional --OR.sup.2.

6. The compound according to claim 3, wherein:

R.sup.3 is selected from the group consisting of C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.5 -C.sub.6 cycloalkyl, C.sub.5 -C.sub.6 cycloalkenyl and Ht, wherein Ht is a 5-6 membered saturated or unsaturated heterocycle, and wherein any member of said R.sup.3 is optionally substituted with one to two substituents independently selected from the group consisting of --OR.sup.2, --C(O)--NH--R.sup.2, --S(O).sub.n N(R.sup.2)(R.sup.2).sub.2, Ht, --CN, --SR.sup.2, --C(O).sub.2 R.sup.2, and NR.sup.2 --C(O)--R.sup.2 ; and

D' is selected from the group consisting of C.sub.1 -C.sub.3 alkyl and C.sub.3 alkenyl, wherein said alkyl or alkenyl is substituted with one to two groups independently selected from the group consisting of C.sub.3 -C.sub.6 cycloalkyl, --O--R.sup.7 and R.sup.7, and optionally substituted with one additional --OR.sup.2.

7. A compound selected from the group consisting of:

4-Fluoro-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-N-isobutyl-benzenesulfonamide (compound 35);

3,4-Dichloro-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-N-isobutyl-benzenesulfonamide (compound 37);

N-(4-(((2 syn,3S)-2-Hydroxy-4-phenyl-3-(pyridin-3-yl-methoxycarbonylamino)-butyl)-is obutyl-sulfamoyl)-phenyl)acetamide (compound 44);

2. 4-Dimethyl-thiazole-5-sulfonic acid-(1,1-dimethyl-ethoxycarbonylamino)-(2 syn,3S)-2-hydroxy-4-phenyl-buty l)-isobutyl-amide (compound 46);

N-(4-(((2 syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-isobutyl-sulfamoyl)-phenyl)-acetamide (compound 48);

4-Fluoro-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-((R)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-N-isobutyl-benzenesulfonamide and 4-Fluoro-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-((R)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-N-isobutyl-benzenesulfonamide (compounds 52);

Benzo(1,2,5)oxadiazole-5-sulfonic acid ((2 syn,3S)-2-hydroxy-4-phenyl-3-(pyridin-3-yl-methoxycarbonylamino)-butyl)-is obutylamide (compound 66);

N-(4-(((2 syn,3S)-2-Hydroxy-4-phenyl-3-((R)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-isobutyl-sulfamoyl-phenyl)-acetamide and N-(4-(((2 syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-isobutyl-sulfamoyl)-phenyl)-acetamide (compounds 86);

N-(2-Fluoro-5-(((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-isobutyl-sulfamoyl)-phenyl)-acetamide (compound 88);

N-(3-(((2 syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-isobutyl-sulfamoyl)-phenyl)-acetamide (compound 91);

4-Fluoro-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-((R)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-N-isobutyl-benzenesulfonamide (compound 93);

N-(4-(((syn)-2-Hydroxy-(S)-4-phenyl-3-((tetrahydrofuran-(R)-3-yl)-oxycarbon ylamino)-butyl)-isobutyl-sulfamoyl)-phenyl)-acetamide (compound 94);

4-Fluoro-N-(2 syn,3S)-2-hydroxy-4-phenyl-3-((tetrahydro-furan-(R)-3-ylmethoxycarbonylami no)-butyl)-N-isobutyl-benzenesulfonamide and 4-Fluoro-N-(2 syn,3S)-2-hydroxy-4-phenyl-3-((tetrahydro-furan-(S)-3-ylmethoxycarbonylami no)-butyl)-N-isobutyl-benzenesulfonamide (compounds 97);

4-Fluoro-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-(pyridin-3-yl-methoxycarbonylamino)-butyl)-N- isobutyl-benzenesulfonamide (compound 98);

4-Chloro-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-isobutyl-benzenesulfonamide (compound 99);

N-((2 syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-N-isobutyl-4-methoxy-benzenesulfonamide (compound 100);

4-Fluoro-N-(2-(syn)-hydroxy-3-((2-oxazolidon-(S)-4-yl)-methoxycarbonylamino )-4-(S)-phenyl-butyl)-N-isobutyl-benzenesulfonamide (compound 109);

Benzene-1,3-disulfonic acid 1-amide 3-((2 syn,3S)-2-hydroxy-4-phenyl-3-(3-(S)-tetrahydrofuran-3-yloxycarbonylamino)- butyl)-isobutyl-amide (compound 112);

Furan-3-sulfonic acid (2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-isobutyl-amide (compound 113);

N-((3-Allyloxycarbonylamino)-(2 syn,3S)-2-hydroxy-4-phenyl-butyl)-N-cyclopentylmethyl-4-fluoro-benzenesulf onamide (compound 114);

N-Cyclopentylmethyl-N-((3-ethoxycarbonylamino)-(2 syn,3S)-2-hydroxy-4-phenyl-butyl)-4-fluoro-benzenesulfonamide (compound 115);

4-Chloro-N-cyclopentylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-benzenesulfonamide (compound 116);

4-Chloro-N-cyclopentylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-(pyridin-3yl-methoxycarbonyl)-butyl)-benzenes ulfonamide (compound 118);

N-(4-(Cyclopentylmethyl-((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-sulfamoyl)-phenyl)-acetamide (compound 125);

3-Chloro-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-N-isobutyl-benzenesulfonamide (compound 138);

4-Chloro-N-cyclopentylmethyl-N-(2-(syn)-hydroxy-3-((2-oxazolidon-4-(S)-yl-m ethyl)-oxycarbonylamino)-4-phenyl-butyl)-benzenesulfonamide (compound 139);

N-cyclopentylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-4-methoxy-benzenesulfonamide (compound 140);

N-((3-allyloxycarbonylamino)-(2 syn,3S)-2-hydroxy-4-phenyl-butyl)-N-cyclopentylmethyl-4-methoxy-benzenesul fonamide (compound 141);

N-Cyclopentylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-(3-pyridin-3-yl-methoxycarbonylamino)-butyl-4 -methoxy-benzenesulfonamide (compound 142);

Pyridine-3-sulfonic acid ((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-isobutyl-amide, trifluoroacetic acid salt (compound 144);

5-Isoxazol-3-yl-thiophene-2-sulfonic acid ((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-isobutyl-amide (compound 145);

N-(4-((3-(Allyloxycarbonylamino)-(2 syn,3S)-2-hydroxy-4-phenyl-butyl)-cyclopentylmethylsulfamoyl)-phenyl)-acet amide (compound 146);

N-(4-(Cyclopentylmethyl-((2 syn,3S)-2-hydroxy-4-phenyl-3-(pyridin-3-yl-methoxycarbonylamino)-butyl)-su lfamoyl)-phenyl)-acetamide (compound 147);

N-Cyclopentylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-benzenesulfonamide (compound 148);

Pyridine-3-sulfonic acid cyclopentylmethyl-((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-amide (compound 149);

Piperidine-1-sulfonic acid ((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-isobutyl-amide (compound 150);

N-4-((2-(syn)-Hydroxy-3-((2-methoxymethyl-allyloxycarbonylamino)-4-(S)-phen yl-butyl)-isobutyl-sulfamoyl)-phenyl)-acetamide (compound 155);

1-Acetyl-2,3-dihydro-1H-indole-6-sulfonic acid ((allyloxycarbonylamino)-(2 syn,3S)-2-hydroxy-4-phenyl-butyl)-cyclopentylmethyl-amide (compound 156);

1-Acetyl-2,3-dihydro-1H-indole-6-sulfonic acid cyclopentylmethyl-((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-amide (compound 157);

N-Cyclohexylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-4-methoxy-benzenesulfonamide (compound 158);

N-Cyclohexylmethyl-4-fluoro-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-benzenesulfonamide (compound 159);

N-(4-(Cyclohexylmethyl)-((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-sulfamoyl-phenyl)-acetamide (compound 160);

N-((2 syn,3S)-2-Hydroxy-4-phenyl-3-(pyridin-4-yl-methoxycarbonylamino)-butyl)-N- isobutyl-4-methoxy-benzenesulfonamide (compound 163);

N-((2 syn,3S)-2-Hydroxy-4-phenyl-3-((syn)-tetrahydrofuran-3-yloxycarbonylamino)- butyl)-N-isobutyl-4-methyl-benzenesulfonamide (compound 165);

N-cyclopentylmethyl-4-hydroxy-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-(pyridin-3-yl-methoxycarbonylamino)-butyl)-be nzenesulfonamide (compound 166);

N-((2 syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-N-isobutyl-4-nitro-benzenesulfonamide (compound 167);

4-Amino-N-((2 syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-N-isobutyl-benzenesulfonamide (compound 168);

N-Cyclopentylmethyl-4-hydroxy-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-benzenesulfonamide (compound 169);

N-Cyclopentylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-4-nitro-benezensulfonamide (compound 170);

4-Amino-N-cyclopentylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-benzenesulfonamide (compound 171);

2,4-Diamino-N-cyclopentylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-benzenesulfonamide (compound 173);

4-Hydroxy-N-(2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-N-isobutyl-benzenesulfonamide (compound 175);

N-Cyclopentylmethyl-4-fluoro-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-benzenesulfonamide (compound 182);

3,4-Dichloro-N-cyclopentylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-benzenesulfonamide (compound 183);

Benzyloxycarbonyl-(L)-isoleucine-N-(5-((3-amino-(2 syn,3S)-2-hydroxy-4-phenyl-butyl)-isobutyl-sulfamoyl)-2-fluoro-phenyl)-ace tamide (compound 187);

N-((4S,2S)-4-Cyclohexyl-2-hydroxy-3-((syn)-tetrahydrofuran-3-yloxycarbonyla mino)-butyl)-N-cyclopentylmethyl-4-methoxy-benzenesulfonamide (compound 195);

N-(4-(((2 syn,3S)-3-(t-Butyldicarbonylamino)-2-hydroxy-4-phenyl-butyl)-isobutyl-sulf amoyl)-phenyl)-acetamide (compound 1001);

N-(4-(((2 syn,3S)-2-Hydroxy-4-phenyl-3-((R)-2-pyrrolidinone-4-ylmethylcarbonylamino) -butyl)-isobutyl-sulfamoyl)-phenyl)-acetamide (compound 1002);

Pyridine-3-sulfonic acid ((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-isobutyl-amide (compound 1003);

3-Amino-4-hydroxy-N-(2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-N-isobutyl-benzenesulfonamide (compound 1004);

N-((2 syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-4-methoxy-N-methylbenzenesulfonamide (compound 1005);

N-((2 syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-4-methoxy-N-(2-methylpropen-2-yl)benzenesulfonamide (compound 1006);

N-((2 syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-N-tetrahydrofuran-2-ylmethyl-4-methoxy-benzenesulfonamide (compound 1007);

N-Furan-2-ylmethyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-4-methoxy-benzenesulfonamide (compound 1008);

N-2,2-Dimethyl-3-hydroxypropyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-4-methoxy-benzenesulfonamide (compound 1009);

N-2-hydroxy-2-methylpropyl-N-((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-4-methoxy-benzenesulfonamide (compound 1010);

N-((2 syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-N-piperidin-4-yl-4-methoxy benzenesulfonamide (compound 1011);

N-((2 syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-N-3-acetylpiperidin-4-yl-4-methoxy benzenesulfonamide (compound 1012);

N-((2 syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-N-piperidin-4-ylmethyl-4-methoxy benzenesulfonamide (compound 1013);

N-((2 syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-N-piperidin-4-ylethyl-4-methoxy benzenesulfonamide (compound 1014); and

3. 4-Diamino-N-((2 syn,3S)-2-Hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-N-isobutyl-benzenesulfonamide (compound 1015).

8. The compound according to claim 1, wherein said compound has a molecular weight less than or equal to about 700 g/mol.

9. A compound according to claim 8, wherein said compound has a molecular weight less than or equal to about 600 g/mol.

10. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to any one of claims 1-3 and a pharmaceutically acceptable carrier, adjuvant or vehicle.

11. A method for treating or preventing a viral disease in a mammal caused by a virus that requires an aspartyl protease for an obligatory life cycle event, said method comprising the step of administering to said mammal a compound according to any one of claims 1-3.

12. The method according to claim 11, wherein said virus is HIV-1, HIV-2, or HTLV.

13. A method for preventing HIV infection in a mammal comprising the step of administering to said mammal a pharmaceutically effective amount of a pharmaceutical composition according to claim 10.

14. A method for treating HIV infection in a mammal comprising the step of administering to said mammal a pharmaceutically effective amount of a pharmaceutical composition according to claim 10.

15. The method according to claim 13 or 14, wherein said step of administering comprises oral administration or administration by injection.

16. The compound according to claim 1, wherein:

R.sup.1 is --O--C(O)--;

each D' is independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl substituted with one to two groups selected from C.sub.3 -C.sub.6 cycloalkyl, --O--R.sup.7 or R.sup.7, and optionally substituted with one additional --OR.sup.2 or --R.sup.3 ; C.sub.2 -C.sub.4 alkenyl substituted with one to two groups selected from C.sub.3 -C.sub.6 cycloalkyl, --O--R.sup.7 or R.sup.7, and optionally substituted with an additional --O.sup.2 or --R.sup.3 ; C.sub.3 -C.sub.6 cycloalkyl, which is optionally substituted with or fused with R.sup.7 ; and C.sub.5 -C.sub.6 cycloalkenyl, which is optionally substituted with or fused with R.sup.7 ; and

E is a 5-membered saturated or unsaturated heterocycle, containing one S and optionally containing N as an additional heteroatom, wherein said heterocycle may optionally be benzofused; and wherein any member of said heterocycle may be optionally substituted with one to two substituents independently selected from the group consisting of oxo, --OR.sup.2, --R.sup.2, --N(R.sup.2)(R.sup.2), --R.sup.2 --OH, ---CN, --CO.sub.2 R, --C(O)--N(R.sup.2)(R.sup.2), --S(O).sub.2 --N(R.sup.2)(R.sup.2), --N(R.sup.2)--C(O)--R.sub.2, --C(O)--R.sup.2, --S(O).sub.n --R.sup.2, --OCF.sub.3, --S(O).sub.n --R.sup.7, methylenedioxy, --N(R.sup.2)--S(O).sub.2 (R.sup.2), halo, --CF.sub.3, --NO.sub.2, R.sup.7 and --O--R.sup.7.

17. The compound according to claim 16, wherein said compound is: ##STR657## 5-Isoxazol-3-yl-thiophene-2-sulfonic acid ((2 syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-bu tyl)-isobutyl-amide (compound 145).

18. The pharmaceutical composition according to claim 10, wherein the viral infection is HIV 1 or HIV 2.
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